A substantial body of data indicates that neuroendocrine factors play a role in the expression of autoimmune diseases such as rheumatoid arthritis. A detailed understanding of these factors should provide important insights into the prevention and therapy of these diseases. We have been conducting studies addressing the role of hypothalamic-pituitary-adrenal (HPA), -gonadal and sympatho-adrenal axes in RA and other forms of early synovitis. We have investigated circadian secretion of ACTH, cortisol and interleukin-(IL)6 in RA patients compared to age-, gender-, and race-matched controls. Overall, ACTH and cortisol secretion were similar in patients and controls, except that RA patients exhibited higher early morning secretion. However, RA patients exhibited substantially higher plasma IL-6 levels. Our data suggest that HPA axis responses are "inappropriately normal" in RA patients. These patients apear to have a relative insensitivity to IL6-stimulated HPA axis activation (LJ Crofford et al., J. Clin. Endocrinol. Metab. 82:1279-1283, 1997). We are doing follow up studies by examining a much larger cohort of patients with various forms of early synovitis. Since deficient HPA function probably has pronounced effects on immune function, we also have been investigating this hypothesis. In particular, we have been exploring the effects of cortisol and other stress mediators on TNF-alpha, IL-12 and IL-10 production by LPS-stimulated blood monocytes. TNF-alpha and IL-12 are prototypic proinflammatory cytokines, whereas IL-10 is a major anti-inflammatory cytokine. We have observed that both cortisol and catecholamines strongly inhibit, through receptor dependent-mechanisms, the secretion of TNF-alpha and IL-12, but cortisol does not significantly suppress secretion of IL-10, and catechoalmines powerfully stimulate IL-10 (Elenkov I et al. Proc. Assoc. Am. Phys 108:374-381, 1996). These observations, indicating contrasting effects of these stress mediators, have important implications on our understanding of the role of neuroendocrine factors in the regulation of inflammatory processes. Additional studies are in progress evaluating these and other mediators, particularly in the context of pregnancy and the postpartum periods.